Human Alpha 1 Antitrypsin Suppresses NF-ĸB Activity and Extends Lifespan in Adult Drosophila

Yuan, Ye; Belkum, Max Van; O’Brien, Alana; Garcia, Alain; Troncoso, Karla; Elshikha, Ahmed S.; Zhou, Lei; Song, Sihong

doi:10.21203/rs.3.rs-1917871/v1

Cited by 2 publications

(1 citation statement)

References 53 publications

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“…It remains to be tested whether the in ammaging pattern of SPH93 is just another phenomenon associated with aging or actively participates in determining the healthspan and lifespan of the animal. It is worth noting that the human serine protease inhibitor AAT suppresses in ammaging and extends both lifespan and healthspan when expressed from the fat body in transgenic fruit ies [10,30]. And this anti-in ammaging function of AAT is independent of its ability to inhibit proteases.…”

Section: Sph93 As a Potential In Ammaging Regulatormentioning

confidence: 99%

Shared Transcriptomic Signatures of Inflammaging Among Diverse Strains of Drosophila melanogaster

Perna,

Tang,

Blimbaum

et al. 2024

Preprint

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Background: A prominent hallmark of aging is inflammaging—the increased expression of innate immune genes without identifiable infection. Model organisms with shorter lifespans, such as the fruit fly, provide an essential platform for probing the mechanisms of inflammaging. Multiple groups have reported that, like mammalian models, old flies have significantly higher levels of expression of anti-microbial peptide genes. However, whether some of these genes—or any others—can serve as reliable markers for assessing and comparing inflammaging in different strains remains unclear. Methods and Results: We compared RNA-Seq datasets generated by different groups. Although the fly strains used in these studies differ significantly, we found that they share a core group of genes with strong aging-associated expression. In addition to anti-microbial peptide genes, we identified other genes that have prominently increased expression in old flies, especially SPH93. We further showed that machine learning models can be used to predict the “inflammatory age” of the fruit fly. Conclusion: A core group of genes may serve as markers for studying inflammaging in Drosophila. RNA-Seq profiles, in combination with machine-learning models, can be applied to measure the acceleration or deceleration of inflammaging.

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Section: Sph93 As a Potential In Ammaging Regulatormentioning

confidence: 99%

Shared Transcriptomic Signatures of Inflammaging Among Diverse Strains of Drosophila melanogaster

Perna,

Tang,

Blimbaum

et al. 2024

Preprint

View full text Add to dashboard Cite

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The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways

Elshikha,

Abboud,

Avdiaj

et al. 2025

Biomolecules

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Endosomal toll-like receptors (TLRs) TLR7, TLR8, and TLR9 play an important role in systemic lupus erythematosus (SLE) pathogenesis. The proteolytic processing of these receptors in the endolysosome is required for signaling in response to DNA and single-stranded RNA, respectively. Targeting this proteolytic processing may represent a novel strategy to inhibit TLR-mediated pathogenesis. Human alpha 1 antitrypsin (hAAT) is a protease inhibitor with anti-inflammatory and immunoregulatory properties. However, the effect of hAAT on endosomal TLRs remains elusive. In this study, we first tested the effect of hAAT on TLR9 signaling in dendritic cells (DCs). We showed that hAAT inhibited TLR9-mediated DC activation and cytokine production. Human AAT also lowered the expressions of interferon signature genes. Western blot analysis showed that hAAT reduced the expression of the active form (cleaved) of TLR9 in DCs, indicating a novel mechanism of hAAT function in the immune system. We next tested the effect of hAAT on TLR7/8 signaling. Similar to the effect on TLR9 signaling, hAAT also inhibited R848 (TLR7 and 8 agonist)-induced DC activation and functions and lowered the expressions of interferon signature genes. Our in vivo studies using hAAT transgenic mice also showed that hAAT attenuated R848-induced pathogenesis. Specifically, hAAT completely blocked the R848 induction of germinal center T cells (GC T), B cells (GC B), and plasma cells (GC PCs), as well as T follicular T helper cells (TFH), which are all critical in lupus development. These data demonstrated that hAAT inhibited TLR7/8 and TLR9 signaling pathways, which are critical for lupus development. These findings not only advanced the current knowledge of hAAT biology, but also implied an insight into the clinical application of hAAT.

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Human Alpha 1 Antitrypsin Suppresses NF-ĸB Activity and Extends Lifespan in Adult Drosophila

Cited by 2 publications

References 53 publications

Shared Transcriptomic Signatures of Inflammaging Among Diverse Strains of Drosophila melanogaster

Shared Transcriptomic Signatures of Inflammaging Among Diverse Strains of Drosophila melanogaster

The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways

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